Volume 207 - Issue 4
Discrepancies in genetic testing results for coeliac disease: call for standardised testing and reporting
Authors: A James M Daveson, Michael Varney, Kate E Jackson and Jason A Tye-Din
Med J Aust 2017; 207 (4): 179-180. || doi: 10.5694/mja17.00314
Published online: 21 August 2017
Published online: 21 August 2017
To the Editor:
The demand for human leukocyte antigen (HLA) typing in the diagnostic work-up of coeliac disease (CD) in Australia has driven a 14-fold rise in testing since 2003 (Medicare Benefits Schedule data, item 71151). Although HLA typing offers limited specificity for CD, its clinical utility results from its exceptional negative predictive value (> 99%) when the specific HLA susceptibility genotypes are not detected.1 Unlike traditional tests for CD, HLA typing results are informative even when the patient is following a gluten free diet. While the accuracy of HLA typing in CD has not been reported, HLA test results are assumed by clinicians to be definitive. Our findings challenge this view.
Discrepancies between several patients’ clinical diagnosis of CD and their negative HLA-DQ2 and -DQ8 typing results in AJD’s practice led to repeat HLA testing with another laboratory. The subsequent reporting of a genotype consistent with CD prompted a clinical audit (2013–2016). Of 211 patients with HLA typing results, nine had been coperformed by two separate laboratories (laboratories 1 and 2), either deliberately or inadvertently. Of these nine patients, six returned conflicting results. An additional DNA sample from all six patients was sent for HLA genotyping by a reference laboratory, where genetic susceptibility for CD was confirmed in five patients (Box). Laboratories 1 and 2 differed in the detection of risk alleles and in the interpretation of or reporting of the results in all six cases. Laboratory 2 identified an at-risk allele in only two of the six patients, and of the four patients with a reported negative genotype, two were subsequently confirmed to have definite CD.
These preliminary findings raise serious concerns about CD HLA testing errors that adversely affect patient care. Although identified in Queensland, these laboratories routinely outsource their HLA typing to laboratories in New South Wales and Victoria, indicating that several Australian states are involved. We are particularly concerned about laboratories new to HLA testing or laboratories that are not participating in stringent quality assessment programs as the sourced reference laboratory does. Therefore, we suggest that an assessment of the performance and quality control measures of all laboratories offering HLA typing is urgently needed. Consistent adoption of evidence-based guidelines that describe optimal HLA testing and reporting1 should form part of the solution.
Box – Human leukocyte antigen (HLA) typing results from three laboratories†
|
Patient |
Laboratory 1 |
Laboratory 2 |
Reference laboratory |
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|
|
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|
Confirmed CD |
“Consistent with DQ2 phenotype; susceptible for CD” |
Genotype not supplied; “Not susceptible for CD” |
HLA-DQ2.2/2.5; susceptible to CD |
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|
Incorrect |
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|
Confirmed CD |
“Consistent with DQ2 phenotype; susceptible for CD” |
Genotype not supplied; “Not susceptible for CD” |
HLA-DQ2.2; susceptible to CD |
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|
Incorrect |
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|
CD excluded |
“Consistent with DQ2 phenotype; susceptible for CD” |
Genotype not supplied; “Not susceptible for CD” |
HLA-DQ2.2; susceptible to CD |
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|
Incorrect |
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|
CD not excluded; on GFD |
“Consistent with DQ8 phenotype; susceptible for CD” |
Genotype not supplied; “Not susceptible for CD” |
No susceptibility to CD detected |
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|
Incorrect |
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|
Normal CD serology |
“DQ2 and DQ8 not identified; no genotype susceptibility for CD” |
“DQA1*0505 has been detected; small percentage susceptible to CD” |
DQA1*05 (HLA-DQ7); low risk susceptibility to CD |
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|
Incorrect |
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|
CD excluded |
“DQ2 and DQ8 not identified; no genotype susceptibility for CD” |
“DQA1*0505 has been detected; small percentage susceptible to CD” |
DQA1*05 (HLA-DQ7); low risk susceptibility to CD |
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|
Incorrect |
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|
|
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CD = coeliac disease. GFD = gluten free diet. ND = not detected. † The reference laboratory was in the Victorian Transplantation and Immunogenetics Service in Melbourne. In addition to the incorrect typing results, laboratory 2 failed to report the specific alleles detected and laboratory 1 failed to distinguish between HLA-DQ2.5 and DQ2.2. |
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Competing interests
Jason Tye-Din is a co-inventor of patents pertaining to the use of gluten peptides in therapeutics, diagnostics and non-toxic gluten; a shareholder of Nexpep; and consultant to ImmusanT. A James Daveson has performed clinical trials for ImmusanT.
References
- Tye-Din JA, Cameron DJ, Daveson AJ, et al. Appropriate clinical use of human leukocyte antigen typing for coeliac disease: an Australasian perspective. Intern Med J 2015; 45: 441-450.